Low Linear Energy Transfer Research Articles

Optical and thermal luminescence efficiencies of BeO exposed to low-energy protons and carbon ions

Optically stimulated luminescence (OSL) and thermoluminescence (TL) are well-described phenomena utilized to measure the absorbed dose of crystalline materials. The techniques are used to monitor low linear energy transfer (LET) radiation (β, γ) as well as high-LET heavy charged particles (HCPs). Detector efficiency ƞdet, defined as the ratio of the luminescence per unit dose from a non-reference radiation field compared to the identical quantity from the reference field, is particle and energy dependent. The responses of BeO ceramics exposed to low-energy HCPs were investigated in this work. Dosimeters were bombarded with 1, 2, and 4 MeV protons, as well as 2 and 4 MeV carbon ions; these radiation qualities constitute a mean LET range of 37.6 keV/μm - 628 keV/μm and were realized using the 2 MV tandem Pelletron particle accelerator at East Carolina University. Each dosimeter was calibrated using a dose response constructed with a90Sr/90Y β source, which was calibrated against a137Cs γ source. This enabled ƞdet to be calculated. It was observed that optical and thermal signal shape and magnitude depend on the mean LET. Furthermore, thermal efficiencies are significantly higher than optical efficiencies for all ions investigated.

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

Proceedings to the 7th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA)

Proceedings to the 7th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA)

РАСЧЁТНАЯ МОДЕЛЬ ВОЗДЕЙСТВИЯ НА ЧЕЛОВЕКА РАДИАЦИОННОГО ОБЛУЧЕНИЯ

Purpose: The aim of the work is to assess the output of stochastic and deterministic effects depending on the effective dose. Material and methods: To construct a model for estimating the probability the output of stochastic and deterministic effects depending on the effective dose of radiation, the literature experimental data were used and the probabilistic-statistical method and the least squares method were used. Results: A mathematical model is developed for estimating the yield of stochastic and deterministic effects depending on the effective radiation dose. A probabilistic mathematical model allows you to convert the risks of deterministic effects due to acute exposure of a person at a high dose and with a small exposure, measured in minutes, to the risks of stochastic effects due to exposure to a small dose during a long exposure (traced or fractionated exposure). The excellent convergence of the predicted (calculated) value EAR1 = 0,000607 and statistical EAR0 = 0.000724 is due to the fact that the reference points LD10 = 2 Gy, LD50/60 = 4 Gy, LD90 = 6 Gy are based on repeatedly verified statistical data on radiation accidents and deaths of more than 1000 people in radiation accidents. This indicates that the mathematical model adequately reflects the output of stochastic and deterministic effects observed in the operation of nuclear facilities both in normal mode and in radiation accidents. Conclusion: The probability of the yield of stochastic and deterministic effects depending on the dose of radiation received by a person is presented. The threshold of the stochastic effect for humans is in the vicinity of the equivalent dose of 10 mSv at a dose rate of 10 mSv / year for radiation with low linear energy transfer. Moreover, the probability of a stochastic effect coming out is 3×10–6 on average after 15 years.

Particle radiotherapy and molecular therapies: mechanisms and strategies towards clinical applications.

Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy.

Radiation cancer risk at different dose rates: new dose-rate effectiveness factors derived from revised A-bomb radiation dosimetry data and non-tumor doses.

The dose rate of atomic bomb (A-bomb) radiation to the survivors has still remained unclear, although the dose–response data of A-bomb cancers has been taken as a standard in estimating the cancer risk of radiation and the dose and dose-rate effectiveness factor (DDREF). Since the applicability of the currently used DDREF of 2 derived from A-bomb data is limited in a narrow dose-rate range, 0.25-75 Gy/min as estimated from analysis of DS86 dosimetry data in the present study, a non-tumor dose (Dnt) was applied in an attempt to gain a more universal dose-rate effectiveness factor (DREF), where Dnt is an empirical parameter defined as the highest dose at which no statistically significant tumor increase is observed above the control level and its magnitude depends on the dose rate. The new DREF values were expressed as a function of the dose rate at four exposure categories, i.e. partial body low LET, whole body low linear energy transfer (LET), partial body high LET and whole body high LET and provided a value of 14 for environmental level radiation at a dose rate of 10−9 Gy/min for whole body low LET.

Mutagenic Effect of Proton Beams Characterized by Phenotypic Analysis and Whole Genome Sequencing in Arabidopsis.

Protons may have contributed to the evolution of plants as a major component of cosmic-rays and also have been used for mutagenesis in plants. Although the mutagenic effect of protons has been well-characterized in animals, no comprehensive phenotypic and genomic analyses has been reported in plants. Here, we investigated the phenotypes and whole genome sequences of Arabidopsis M2 lines derived by irradiation with proton beams and gamma-rays, to determine unique characteristics of proton beams in mutagenesis. We found that mutation frequency was dependent on the irradiation doses of both proton beams and gamma-rays. On the basis of the relationship between survival and mutation rates, we hypothesized that there may be a mutation rate threshold for survived individuals after irradiation. There were no significant differences between the total mutation rates in groups derived using proton beam or gamma-ray irradiation at doses that had similar impacts on survival rate. However, proton beam irradiation resulted in a broader mutant phenotype spectrum than gamma-ray irradiation, and proton beams generated more DNA structural variations (SVs) than gamma-rays. The most frequent SV was inversion. Most of the inversion junctions contained sequences with microhomology and were associated with the deletion of only a few nucleotides, which implies that preferential use of microhomology in non-homologous end joining was likely to be responsible for the SVs. These results show that protons, as particles with low linear energy transfer (LET), have unique characteristics in mutagenesis that partially overlap with those of low-LET gamma-rays and high-LET heavy ions in different respects.

Gadolinium delivery agents for neutron capture therapy

<p indent=0mm>Neutron capture therapy (NCT) is a binary form of radiation therapy that combines neutron irradiation with a tumor targeting agent labeled with a stable isotope having a high thermal neutron capture cross section and yielding charged particle reaction products after neutron capture. At present, NCT has largely, but not exclusively, focused on the use of boron-10 as the target nuclide. Gadolinium neutron capture therapy (Gd-NCT) is an alternative and supplementary method of boron neutron capture therapy (BNCT). Gd-157, which has the largest cross-section (254000 barn) of thermal neutrons of all stable isotopes, is the most effective isotope in terms of neutron capture. The Gd neutron capture reaction, ¹⁵⁷Gd(n, γ)¹⁵⁸Gd, provokes complicated nuclear decay transitions that generate low linear energy transfer (LET) gamma photons and the emission of high LET conversion electrons and Auger electrons. Therefore, Gd is considered to be highly suitable for the absorption of thermal neutrons in the NCT reaction. Another advantage of Gd-NCT is Gd³⁺ has a longer retention time and can thus be tracked by means of magnetic resonance imaging (MRI) methods. Currently, Gd(III) based MRI contrast agents are most commonly used in clinical practice. However, due to lack of appropriate tumor-selective Gd agents, the Gd-NCT concept has not yet been clinically tested. For a successful neutron capture therapy, a target nuclide delivery system with high therapeutic efficiency and low adverse effects is crucial. Three major classes Gd delivery agents have been developed so far, small molecule chelates of Gd, nano- delivery agents, and Gd-B dual delivery agents. In the first trial of Gd-NCT, commercially available MRI contrast agents composed of Gd-chelating compounds were used as Gd delivery agents. However, due to the insufficient number of tumor cell nuclei incorporating Gd, efficacy of small molecule chelates of Gd as Gd-NCT delivery agents is generally low. In recent years, with the rapid development of nanotechnology, nanomaterials have been widely employed as carriers for cancer theranostics. A variety of Gd-based nanomaterials have been developed for pre-clinical trials of NCT. Majority of them are constructed by incorporating commercially available MRI contrast agents in biocompatible nanomaterials (liposomes, albumin, and micelles), or employing Gd based nanoparticles with their unique physiochemical properties. While nano-Gd delivery agents have proved to be a promising strategy in Gd-NCT, it is also possible to integrate of both Gd and B in one delivery agent. The design of many Gd-NCT agents to date has focused on combined BNCT and Gd-NCT agents in order to maximise cytotoxicity from the combined effects or to use the B component for NCT and the Gd component as a MRI imaging agent. This paper highlights the recent advances in Gd selective and efficient delivery methods and the preclinical outcome of Gd-NCT, both advantages and disadvantages of various Gd delivery agents were addressed. Finally, we offered our perspectives on the challenges and future development of Gd delivery agents for Gd-NCT.

Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

Monte Carlo multi-track chemistry simulations were carried out to study the effects of high dose rates on the transient yields of hydronium ions (H3O+) formed during low linear energy transfer (LET) radiolysis of both pure, deaerated and aerated liquid water at 25 °C, in the interval ∼1 ps – 10 μs. Our simulation model consisted of randomly irradiating water with N interactive tracks of 300-MeV incident protons (LET ∼ 0.3 keV/µm), which simultaneously impact perpendicularly on the water within a circular surface. The effect of the dose rate was studied by varying N. Our calculations showed that the radiolytic formation of H3O+ causes the entire irradiated volume to temporarily become very acidic. The magnitude and duration of this abrupt “acid-spike” response depend on the value of N. It is most intense at times less than ∼10–100 ns, equal to ∼3.4 and 2.8 for N = 500 and 2000 (i.e., for dose rates of ∼1.9 × 109 and 8.7 × 109 Gy/s, respectively). At longer times, the pH gradually increases for all N values and eventually returns to the neutral value of seven, which corresponds to the non-radiolytic, pre-irradiation concentration of H3O+. It is worth noting that these early acidic pH responses are very little dependent on the presence or absence of oxygen. Finally, given the importance of pH for many cellular functions, this study suggests that these acidic pH spikes may contribute to the normal tissue-sparing effect of FLASH radiotherapy.

Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response.

Simple SummaryRadiation therapy can modulate anti-tumor immune responses. In this study, we investigated the relationship between the anti-tumor immune response and tumor fibrosis after X-ray or neutron radiation therapy. Neutron radiation therapy resulted in lesser fibrosis and greater anti-tumor immunity compared to X-ray irradiation. Radiation therapy-induced fibrotic changes within the tumor environment and tumor regrowth were suppressed by specifically deleting Trp53 in endothelial cells. In particular, the upregulation of PD-L1 expression after X-ray radiation therapy was significantly suppressed via EC-Trp53 deletion. Understanding the effects of different radiation therapy types on the tumor microenvironment provides strategies for enhancing the efficacy of combined radio- and immunotherapy. High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth.

Analysis of Ion-Induced SEFI and SEL Phenomena in 90 nm NOR Flash Memory

This article mainly focuses on the single event function interruption (SEFI) and single event latch-up (SEL) of 90 nm NOR flash memories. Devices were irradiated by ions with different linear energy transfer (LET) values from 12.9 to $65.8~MeV\cdot cm^{2}$ /mg. SEFI observed in the device is further divided into bit SEFI, column SEFI, and sector SEFI by severity of data corruption. Under irradiation with low LET value ions, SEL propagation-like phenomena were observed in this work, which was recognized as the process from local latch-up to global latch-up in the peripheral circuits. The underlying mechanisms for SEFI and SEL in NOR flash are discussed. Results indicate that the radiation-induced transient current should be responsible for SEFI, and different forms of SEFI depend on in which part of the circuit that transient current occurred. Besides, SEL in NOR flash is considered to be triggered from the peripheral circuits.

Modeling of cellular response after FLASH irradiation: a quantitative analysis based on the radiolytic oxygen depletion hypothesis

Purpose. Recent studies suggest ultra-high dose rate (FLASH) irradiation can spare normal tissues from radiotoxicity, while efficiently controlling the tumor, and this is known as the ‘FLASH effect’. This study performed theoretical analyses about the impact of radiolytic oxygen depletion (ROD) on the cellular responses after FLASH irradiation. Methods. Monte Carlo simulation was used to model the ROD process, determine the DNA damage, and calculate the amount of oxygen depleted (L ROD) during FLASH exposure. A mathematical model was applied to analyze oxygen tension (pO2) distribution in human tissues and the recovery of pO2 after FLASH irradiation. DNA damage and cell survival fractions (SFs) after FLASH irradiation were calculated. The impact of initial cellular pO2, FLASH pulse number, pulse interval, and radiation quality of the source particles on ROD and subsequent cellular responses were systematically evaluated. Results. The simulated electron L ROD range was 0.38–0.43 μM Gy−1 when pO2 ranged from 7.5 to 160 mmHg. The calculated DNA damage and SFs show that the radioprotective effect is only evident in cells with a low pO2. Different irradiation setups alter the cellular responses by modifying the pO2. Single pulse delivery or multi-pulse delivery with pulse intervals shorter than 10–50 ms resulted in fewer DNA damages and higher SFs. Source particles with a low linear energy transfer (LET) have a higher capacity to deplete oxygen, and thus, lead to a more conspicuous radioprotective effect. Conclusions. A systematic analysis of the cellular response following FLASH irradiation was performed to provided suggestions for future FLASH applications. The FLASH radioprotective effect due to ROD may only be observed in cells with a low pO2. Single pulse delivery or multi-pulse delivery with short pulse intervals are suggested for FLASH irradiation to avoid oxygen tension recovery during pulse intervals. Source particles with low LET are preferred for their conspicuous radioprotective effects.

An approach to assessing the contribution of the high LET effect in strategies for Auger endoradiotherapy

Purpose: The interest in exploiting Auger emitters in cancer therapy stems from their high linear energy transfer (LET) – type radiation damage. However, the design of Auger-emitter labelled vehicles, that target the Auger cascade specifically to tumour cells, is challenging, especially to bring the decay event close enough to DNA to inflict high LET– type damage in DNA. Here we suggest a possible approach to evaluate tumour-targeting Auger-labelled conjugates by assessing the impact of a radioprotector known to be effective in protecting low LET radiation, but ineffective in protecting against high LET-type radiation. However, the efficacy of the radioprotector is not known in the context of irradiation by low energy electrons from randomly distributed Auger emitters. Given some similarity between the energy spectrum of Auger electrons and that of secondary electrons from soft X-rays, we report the results of radioprotection experiments with 25 kVp X-rays. Materials and methods: Clonogenic survival curves for cultured human keratinocytes were established for three different irradiation conditions: 137Cs γ-rays, 25 keV X-rays (effective energy 15.5 keV) and 320 kVp X-rays, and the effect of including a new methylproamine analogue, denoted “2PH”, before and during irradiation, was investigated. Results: The extent of radioprotection by 2PH was essentially the same for all radiation conditions, although RBE was higher (about 1.7) for soft X-rays. This suggests that the effects of randomly distributed Auger emitters will be largely subject to radioprotection. Conclusions: It is reasonable to expect that use of methylproamine analogues will help to ascertain the relative contributions of the high-LET effects (not protected), compared to other components, including bystander effects, that are subject to radioprotection. This could be a useful tool in evaluating Auger endoradiotherapy strategies.

TOPAS-nBio validation for simulating water radiolysis and DNA damage under low-LET irradiation

The chemical stage of the Monte Carlo track-structure simulation code Geant4-DNA has been revised and validated. The root-mean-square (RMS) empirical parameter that dictates the displacement of water molecules after an ionization and excitation event in Geant4-DNA has been shortened to better fit experimental data. The pre-defined dissociation channels and branching ratios were not modified, but the reaction rate coefficients for simulating the chemical stage of water radiolysis were updated. The evaluation of Geant4-DNA was accomplished with TOPAS-nBio. For that, we compared predicted time-dependent G values in pure liquid water for ·OH, e– aq, and H2 with published experimental data. For H2O2 and H·, simulation of added scavengers at different concentrations resulted in better agreement with measurements. In addition, DNA geometry information was integrated with chemistry simulation in TOPAS-nBio to realize reactions between radiolytic chemical species and DNA. This was used in the estimation of the yield of single-strand breaks (SSB) induced by 137Cs γ-ray radiolysis of supercoiled pUC18 plasmids dissolved in aerated solutions containing DMSO. The efficiency of SSB induction by reaction between radiolytic species and DNA used in the simulation was chosen to provide the best agreement with published measurements. An RMS displacement of 1.24 nm provided agreement with measured data within experimental uncertainties for time-dependent G values and under the presence of scavengers. SSB efficiencies of 24% and 0.5% for ·OH and H·, respectively, led to an overall agreement of TOPAS-nBio results within experimental uncertainties. The efficiencies obtained agreed with values obtained with published non-homogeneous kinetic model and step-by-step Monte Carlo simulations but disagreed by 12% with published direct measurements. Improvement of the spatial resolution of the DNA damage model might mitigate such disagreement. In conclusion, with these improvements, Geant4-DNA/TOPAS-nBio provides a fast, accurate, and user-friendly tool for simulating DNA damage under low linear energy transfer irradiation.

Meso-scale Discovery Assay Detects the Changes of Plasma Cytokine Levels in Mice after Low or High LET Ionizing Irradiation

ObjectiveTo obtain precise data on the changes in the levels of 29 cytokines in mice after high or low linear energy transfer (LET) irradiation and to develop an accurate model of radiation exposure based on the cytokine levels after irradiation. MethodsPlasma samples harvested from mice at different time points after carbon-ion or X-ray irradiation were analyzed using meso-scale discovery (MSD), a high-throughput and sensitive electrochemiluminescence measurement technique. Dose estimation equations were set up using multiple linear regression analysis. ResultsThe relative levels of IL-6 at 1 h, IL-5 and IL-6 at 24 h, and IL-5, IL-6 and IL-15 at 7 d after irradiation with two intensities increased dose-dependently. The minimum measured levels of IL-5, IL-6 and IL-15 were up to 4.0076 pg/mL, 16.4538 pg/mL and 0.4150 pg/mL, respectively. In addition, dose estimation models were established and verified. ConclusionsThe MSD assay can provide more accurate data regarding the changes in the levels of the cytokines IL-5, IL-6 and IL-15. These cytokines could meet the essential criteria for radiosensitive biomarkers and can be used as radiation indicators. Our prediction models can conveniently and accurately estimate the exposure dose in irradiated organism.

Structural and dosimetric study of sub-kGy neutron-irradiated graphitic media

Associated with the marked difference between the mechanism of neutrons interactions relative to that of low linear-energy transfer (LET) radiations, few convenient dosimeters offer well differentiated measurement of neutron doses at useful sensitivity and spatial resolution. Present study has made use of highly uniform 2B and HB grade polymer pencil lead graphite (PPLG) (approximately 95 wt % and 61 wt % graphite content, respectively), addressing variation in lattice structure and defects resulting from sub-kGy neutron-doses. The latter have been provided by the TRIGA-II nuclear reactor located at the Bangladesh Atomic Energy Commission. Raman, photoluminescence (PL), and thermoluminescence (TL) techniques were used to perform structural and luminescence characterization of PPLGs. Comparison was made with highly-oriented pyrolytic graphite (HOPG), a pure ordered synthetic form of graphite. The dose-dependent defects produced in graphitic structures were characterized based on the Raman ID/IG intensity ratio, with observation of the Wigner effect. Analysis of PL spectra provides an average band gap energy in the range of 1.111–1.114 eV. All samples have been found to provide excellent linear response within the dose range 0–200 Gy, 2B grade PPLGs showing greater sensitivity compared to that of HB. The outcomes from this research may contribute to the development of cost effective, versatile graphite-based dosimeters, with particular applications to ionizing radiation dosimetry in clinical radiotherapy and industrial spheres.

High LET-Like Radiation Tracks at the Distal Side of Accelerated Proton Bragg Peak.

Proton therapy is a type of hadron radiotherapy used for treating solid tumors. Unlike heavy charged elements, proton radiation is considered to be low LET (Linear Energy Transfer) radiation, like X-rays. However, the clinical SOBP (Spread Out Bragg Peak) proton radiation is considered to be higher in relative biological effectiveness (RBE) than both X-ray and their own entrance region. The RBE is estimated to be 1.1–1.2, which can be attributed to the higher LET at the SOBP region than at the entrance region. In order to clarify the nature of higher LET near the Bragg peak of proton radiation and its potential cytotoxic effects, we utilized a horizontal irradiation system with CHO cells. Additionally, we examined DNA repair mutants, analyzed cytotoxicity with colony formation, and assessed DNA damage and its repair with γ-H2AX foci assay in a high-resolution microscopic scale analysis along with the Bragg peak. Besides confirming that the most cytotoxic effects occurred at the Bragg peak, extended cytotoxicity was observed a few millimeters after the Bragg peak. γ-H2AX foci numbers reached a maximum at the Bragg peak and reduced dramatically after the Bragg peak. However, in the post-Bragg peak region, particle track-like structures were sporadically observed. This region contains foci that are more difficult to repair. The peak and post-Bragg peak regions contain rare high LET-like radiation tracks and can cause cellular lethality. This may have caused unwanted side effects and complexities of outputs for the proton therapy treatment.

Update of the particle irradiation data ensemble (PIDE) for cell survival.

The particle irradiation data ensemble (PIDE) is the largest database of cell survival data measured after exposure to ion beams and photon reference radiation. We report here on the updated version of the PIDE database and demonstrate how to investigate generic properties of radiation dose response using these sets of raw data. The database now contains information of over 1100 pairs of photon and ion dose response curves. It provides the originally published raw data of cell survival in addition to given linear quadratic (LQ) model parameters. If available, the raw data were used to derive LQ model parameters in the same way for all experiments. To demonstrate the extent of the database and the variability among experiments we focus on the dose response curves after ion and photon radiation separately in a first step. Furthermore, we discuss the capability and the limitations of the database for analyzing properties of low and high linear energy transfer (LET) radiation response based on multiple experiments. PIDE is freely available to the research community under www.gsi.de/bio-pide.

Synergistic Effects of Chronic Restraint-Induced Stress and Low-Dose 56Fe-particle Irradiation on Induction of Chromosomal Aberrations in Trp53-Heterozygous Mice.

Astronauts can develop psychological stress (PS) during space flights due to the enclosed environment, microgravity, altered light-dark cycles, and risks of equipment failure or fatal mishaps. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. Psychological stress or radiation exposure can cause detrimental effects in humans. An earlier published pioneering study showed that chronic restraint-induced psychological stress (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by low-linear energy transfer (LET) γ rays in Trp53-heterozygous (Trp53+/-) mice. To elucidate possible modification effects from CRIPS on high-LET HZE particle-induced health consequences, Trp53+/- mice were received both CRIPS and accelerated Fe ion irradiation. Six-week-old Trp53+/- C57BL/6N male mice were restrained 6 h per day for 28 consecutive days. On day 8, they received total-body Fe-particle irradiation (Fe-TBI, 0.1 or 2 Gy). Metaphase chromosome spreads prepared from splenocytes at the end of the 28-day restraint regimen were painted with the fluorescence in situ hybridization (FISH) probes for chromosomes 1 (green), 2 (red) and 3 (yellow). Induction of psychological stress in our experimental model was confirmed by increase in urinary corticosterone level on day 7 of restraint regimen. Regardless of Fe-TBI, CRIPS reduced splenocyte number per spleen at the end of the 28-day restraint regimen. At 2 Gy, Fe-TBI alone induced many aberrant chromosomes and no modifying effect was detected from CRIPS on induction of aberrant chromosomes. Notably, neither Fe-TBI at 0.1 Gy nor CRIPS alone induced any increase in the frequency of aberrant chromosomes, while simultaneous exposure resulted in a significant increase in the frequency of chromosomal exchanges. These findings clearly showed that CRIPS could enhance the frequency of chromosomal exchanges induced by Fe-TBI at a low dose of 0.1 Gy.

CircZNF208 enhances the sensitivity to X-rays instead of carbon-ions through the miR-7-5p /SNCA signal axis in non-small-cell lung cancer cells

BackgroundMounting evidence suggests that circular RNAs (circRNAs) are closely related to the regulation of gene expression during tumour development. However, the role of circRNAs in modulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells has not been explored. MethodsTranscriptome sequencing was used to explore the expression profiles of circRNAs in NSCLC. The expression level of circRNAs was changed by inducing instantaneous knockdown or overexpression. Changes in proliferation and radiosensitivity of NSCLC cells were investigated using CCK-8, EDU, and clonal survivals. ResultsBy analysing the circRNA expression profile of NSCLC cells, we found that circRNA ZNF208 (circZNF208) was significantly upregulated in a radioresistant NSCLC cell line (A549-R11), which was acquired from the parental NSCLC cell line A549. Knockout experiments indicated that circZNF208 enhanced the radiosensitivity of A549 and A549-R11 cells to X-rays. Mechanistically, circZNF208 upregulated SNCA expression by acting as a sponge of miR-7-5p and subsequently promoted the resistance of NSCLC cells to low linear energy transfer (LET) X-rays. However, this effect was not observed in NSCLC cells exposed to high-LET carbon ions. ConclusionsKnockdown of circZNF208 altered the radiosensitivity of patients with NSCLC to X-rays but did not significantly change the sensitivity to carbon ions. Therefore, circZNF208 might serve as a potential biomarker and therapeutic target for NSCLC treatment with radiotherapy of different modalities.